Paeonol reduces microbial metabolite α-hydroxyisobutyric acid to alleviate the ROS/TXNIP/NLRP3 pathway-mediated endothelial inflammation in atherosclerosis mice

Gut microbiota dysbiosis is an avenue for the promotion of atherosclerosis(AS)and this effect is mediated partly via the circulating microbial metabolites.More microbial metabolites related to AS vascular inflammation,and the mechanisms involved need to be clarified urgently.Paeonol(Pae)is an active compound isolated from Paeonia suffruticoas Andr.with anti-As inflammation effect.However,considering the low oral bioavailability of Pae,it is worth exploring the mechanism by which Pae reduces the harmful metabolites of the gut microbiota to alleviate AS.In this study,ApoE--mice were fed a high-fat diet(HFD)to establish an AS model.AS mice were administrated with Pae(200 or 400 mg:kg')by oral gavage and fecal microbiota transplantation(FMT)was conducted.16S rDNA sequencing was performed to investigate the composition of the gut microbiota,while metabolomics analysis was used to identify the metabolites in serum and cecal contents.The results indicated that Pae significantly improved AS by regulating gut microbiota composition and microbiota metabolic profile in AS mice.We also identified a-hydroxyisobutyric acid(HIBA)as a harmful microbial metabolite reduced by Pae.HIBA supplementation in drinking water promoted AS inflammation in AS mice.Furthermore,vascular endothelial cells(VECs)were cultured and stimulated by HIBA.We verified that HIBA stimulation increased intracellular ROS levels,thereby inducing VEC inflammation via the TXNIP/NLRP3 pathway.In sum,Pae reduces the production of the microbial metabolite HIBA,thus alleviating the ROS/TXNIP/NLRP3 pathway-mediated endothelial inflammation in AS.Our study innovatively confirms the mechanism by which Pae reduces the harmful metabolites of gut microbiota to alleviate AS and proposes HIBA as a potential biomarker for AS clinical judgment.

Sterol carrier protein 2: A promising target in the pathogenesis of atherosclerosis

Atherosclerosis, the underlying pathophysiological basis of cardiovascular disease, has been recognized as a lipid-driven chronic inflammatory disease. Sterol carrier protein 2 (SCP-2) is a 13-kDa non-specific lipid-transfer protein expressed by various tissues and cells, such as liver, heart, vascular smooth muscle cells (VSMCs), and macrophages. SCP-2 has an extensive role in cardiovascular and metabolic diseases. Recently, SCP-2 was reported to promote the development of atherosclerosis by regulating lipid metabolism and peroxidation, endocannabinoid metabolism, vascular inflammation, and fatty acid metabolism. In this review, we summarized the recent advances regarding the role of SCP-2 in the pathogenesis of atherosclerosis and tried to provide a rationale for future investigation and a better understanding of the biological functions of SCP-2 in atherosclerotic cardiovascular disease.